Search

Introduction: Severe acute kidney injury (AKI) and chronic kidney disease (CKD) are considered to be uncommon in patients with acquired thrombotic thrombocytopenic purpura. However, a recent case series from a tertiary care hospital indicated that 54 (59%) of 92 patients with thrombotic thrombocytopenic purpura presented with AKI; 14 (15%) required dialysis; and 12 (22%) of the 54 patients had CKD at follow-up., Methods: In this prospective analysis of 78 patients diagnosed with their first episode of thrombotic thrombocytopenic purpura and enrolled in the Oklahoma Thrombotic Thrombocytopenic Purpura Registry from 1995 to 2015, we assessed AKI at diagnosis using Kidney Disease: Improving Global Outcomes criteria, and CKD at follow-up as defined by estimated glomerular filtration rate <60 ml/min per 1.73 m 2 determined by the Chronic Kidney Disease-Epidemiology Collaboration equation., Results: Forty-five (58%) patients had AKI; 8 (10%) had stage 3 AKI, and 3 (4%) required dialysis. AKI was not associated with the patients' demographic or presenting clinical features. Three of the 8 patients with stage 3 AKI died; among the 5 survivors, estimated glomerular filtration rate was 77 to 107 ml/min per 1.73 m 2 (median, 92) with median follow-up of 8.1 years. Among all 62 surviving patients who have had follow-up serum creatinine measurements, 4 (6%) had CKD with median follow-up of 6.4 years. AKI was not associated with the occurrence of CKD ( P  = 0.74). No patients have required continuing renal replacement therapy., Discussion: In this population-based prospective cohort of consecutive patients with thrombotic thrombocytopenic purpura, without selection or referral bias, severe AKI and CKD are uncommon.

Our objective was to describe new observations from the Oklahoma Thrombotic Thrombocytopenic Purpura (TTP) Registry experience (November 1995 through December 2015) on the diagnosis of TTP along with patients' clinical features and their outcomes. Among 363 patients with an initial episode of clinically suspected TTP, the diagnosis of TTP was supported by both ADAMTS13 activity <10% and clinical features in 78 patients (21%). ADAMTS13 activity was measured in all 363 patients by 2 methods: fluorescence resonance energy transfer (FRET) and immunoblotting (IB). Sixty patients had ADAMTS13 activity <10% by both methods, 15 had ADAMTS13 <10% only by FRET, and 3 had ADAMTS13 <10% only by IB. Five patients with ADAMTS13 activity <10% by 1 method had an alternative clinical diagnosis, not TTP. Two patients with characteristic clinical features of TTP (microangiopathic hemolytic anemia and thrombocytopenia, no alternative diagnosis) and multiple relapses initially had ADAMTS13 activity >10% by both measurements. ADAMTS13 inhibitor titers were not associated with presenting features or outcomes. Microangiopathic hemolytic anemia and thrombocytopenia were not severe in all patients. Forty-seven percent of patients had no or minor neurologic abnormalities; 95% had no or minor serum creatinine abnormalities. Ten patients (13%) died, 2 before completing 1 plasma exchange (PEX); 3 deaths were attributed to PEX complications. For patients presenting after we began using rituximab in some patients (December 2003), fewer PEX treatments were required and fewer relapses occurred. Patients with their first relapse presented with higher platelet counts and hematocrits and lower lactate dehydrogenase levels and required fewer PEX treatments compared with their initial episodes., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

The unexpected occurrence of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia and thrombocytopenia, in a patient with cancer requires urgent diagnosis and appropriate management. TMA is a term used to describe multiple syndromes caused by microvascular thrombosis, including thrombotic thrombocytopenic purpura (TTP), Shiga toxin-mediated hemolytic uremic syndrome, and complement-mediated TMA. In patients with cancer, systemic microvascular metastases and bone marrow involvement can cause microangiopathic hemolytic anemia and thrombocytopenia. This occurs most often in patients with known metastatic cancer, but microangiopathic hemolytic anemia and thrombocytopenia may occur unexpectedly in patients without known metastatic disease or be the presenting features of undiagnosed cancer. TMA may also be caused by commonly used chemotherapy agents, either through dose-dependent toxicity or an acute immune-mediated reaction. These causes of TMA must be distinguished from TTP, which results from a severe deficiency of ADAMTS13 and is the most common cause of TMA among adults without cancer. The importance of this distinction is to avoid inappropriate use of plasma exchange, which is associated with major complications. Plasma exchange is the essential treatment for TTP, but it has no known benefit for patients with cancer-induced or drug-induced TMA. We will describe cancer-induced and drug-induced TMA using the experience of the Oklahoma TTP-Hemolytic Uremic Syndrome Registry and data from a systematic review of all published reports of drug-induced TMA. We will illustrate the principles of evaluation and management of these disorders with patients' stories., (Copyright © 2016 by American Society of Clinical Oncology.)

Quinine is a common cause of drug-induced thrombocytopenia and the most common cause of drug-induced thrombotic microangiopathy. Other quinine-induced systemic disorders have been described. To understand the complete clinical spectrum of adverse reactions to quinine we searched 11 databases for articles that provided sufficient data to allow evaluation of levels of evidence supporting a causal association with quinine. Three reviewers independently determined the levels of evidence, including both immune-mediated and toxic adverse reactions. The principal focus of this review was on acute, immune-mediated reactions. The source of quinine exposure, the involved organ systems, the severity of the adverse reactions, and patient outcomes were documented. One hundred-fourteen articles described 142 patients with definite or probable evidence for a causal association of quinine with acute, immune-mediated reactions. These reactions included chills, fever, hypotension, painful acral cyanosis, disseminated intravascular coagulation, hemolytic anemia, thrombocytopenia, neutropenia, acute kidney injury, rhabdomyolysis, liver toxicity, cardiac ischemia, respiratory failure, hypoglycemia, blindness, and toxic epidermal necrolysis. One hundred-two (72%) reactions were caused by quinine pills; 28 (20%) by quinine-containing beverages; 12 (8%) by five other types of exposures. Excluding 41 patients who had only dermatologic reactions, 92 (91%) of 101 patients had required hospitalization for severe illness; 30 required renal replacement therapy; three died. Quinine, even with only minute exposure from common beverages, can cause severe adverse reactions involving multiple organ systems. In patients with acute, multi-system disorders of unknown origin, an adverse reaction to quinine should be considered., (© 2016 Wiley Periodicals, Inc.)

After recovery from an acute episode of acquired thrombotic thrombocytopenic purpura (TTP), patients often describe problems with memory, concentration, and endurance. We have previously reported the occurrence of depression and cognitive impairment in these patients. In this study, we describe the frequency, severity, and clinical course of depression and cognitive impairment. Fifty-two (85%) out of 61 eligible Oklahoma Registry patients who had recovered from TTP, documented by ADAMTS13 activity <10%, have had at least one (median, four) evaluation for depression over 11 years using the Beck Depression Inventory-II; 31 (59%) patients screened positive for depression at least once; in 15 (29%), the results suggested severe depression at least once. Nine of these 15 patients had a psychiatric interview, the definitive diagnostic evaluation; the diagnosis of major depressive disorder was established in eight (89%) patients. In 2014, cognitive ability was evaluated in 33 patients by the Montreal Cognitive Assessment and the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Both tests detected significant cognitive impairment in the patients as a group. Fifteen out of the 33 patients had been evaluated by extensive cognitive tests in 2006. The 2014 RBANS results were significantly worse than the 2006 results for the overall score and two out of the five RBANS domains (immediate and delayed memory). Neither depression nor cognitive impairment was significantly associated with the occurrence of relapses or ADAMTS13 activity <10% during remission. These observations emphasize the importance of screening evaluations for depression and cognitive impairment after recovery from acquired TTP., (© 2015 Wiley Periodicals, Inc.)

Problem: There is a recognized need to translate scientific discoveries to patient-oriented clinical research (POCR). Several obstacles interfere with the successful recruitment and retention of physicians for POCR careers., Approach: The American Society of Hematology developed a yearlong educational and mentoring experience, the Clinical Research Training Institute (CRTI), for early-career physician-scientists from multiple institutions throughout the United States and Canada pursuing POCR careers. Several academic outcome measures of the 140 participants in the first seven years (2003-2010) of CRTI were evaluated by reviewing former trainee participants' curriculum vitae and survey responses., Outcomes: Ethnic, racial, and gender diversity of CRTI trainees was reflective of the proportions represented across U.S. hematology/oncology fellowship programs. Eighty-six percent (109/126) of trainees reported success establishing a POCR study; nearly half (62/126) had primarily research-focused jobs. Former CRTI trainees received at least 262 external grant awards and published 1,035 peer-reviewed manuscripts, 173 chapters, and 115 review articles., Next Steps: Because mentorship is key to developing a successful career, the CRTI program is being modified to enhance longitudinal mentorship by CRTI faculty mentors and mentors at trainees' home institutions, as well as to encourage the establishment of collaborations and the potential for research project success. Efforts to make the CRTI experience available to more phy sicians, include more CRTI graduates as faculty, and increase participation by hematologists from backgrounds under represented in medicine are under way.

Many drugs have been reported to cause thrombotic microangiopathy (TMA), often described as thrombotic thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS). We recently established criteria to evaluate the evidence for a causal association of a drug with TMA and then we systematically reviewed all published reports of drug-induced TMA (DITMA) to determine the level of evidence supporting a causal association of the suspected drug with TMA. On the basis of this experience, we used these evaluation criteria to assess the Oklahoma TTP-HUS Registry patients who had been previously categorized as drug-induced, 1989-2014. We also reviewed the experience of the BloodCenter of Wisconsin with testing for drug-dependent antibodies reactive with platelets and neutrophils in patients with suspected immune-mediated DITMA, 1988-2014. Among 58 patients in the Oklahoma Registry previously categorized as drug-induced (15 suspected drugs), 21 patients (three drugs: gemcitabine, pentostatin, quinine) had evidence supporting a definite association with TMA; 19 (90%) of the 21 patients had quinine-induced TMA. The BloodCenter of Wisconsin tested 40 patients with suspected DITMA (eight drugs); drug-dependent antibodies, supporting a definite association with TMA, were identified in 30 patients (three drugs: oxaliplatin, quinine, vancomycin); 28 (93%) of the 30 patients had quinine-induced TMA. Combining the data from these two sources, 51 patients (five drugs) have been identified with evidence supporting a definite association with TMA. DITMA was attributed to quinine in 47 (92%) of these 51 patients., (© 2015 Wiley Periodicals, Inc.)

Background: Evans syndrome is a rare condition manifested by combined autoimmune hemolytic anemia (AIHA) and thrombocytopenia or neutropenia. It is often associated with other autoimmune disorders, immunodeficiencies, and non-Hodgkin's lymphoma., Case Report: We describe a patient with Evans syndrome that may have been related to exposure to a polyethylene-based intrauterine contraceptive device (IUD). A 26-year-old white female presented with severe, symptomatic AIHA and subsequently developed severe thrombocytopenia. She had a refractory course resistant to multiple treatments including corticosteroids, intravenous immune globulin, rituximab, splenectomy, cyclophosphamide, cyclosporine, eculizumab, and plasma exchange. It was then noticed that her serum autoantibody agglutinated red blood cells (RBCs) in the presence of polyethylene glycol (PEG) but not in the absence of PEG nor when an alternative agglutination enhancing technique, low-ionic-strength solution, was used. Therefore, her polyethylene-containing IUD, which was a polyethylene frame with a levonorgestrel-releasing device, was removed. Norgestrel-dependent, platelet (PLT)-reactive antibodies were not identified by either flow cytometry or in vivo in a NOD/SCID mouse. Testing for PEG-dependent antibodies was not possible. Remission, with no requirement for RBC or PLT transfusions and return of her hemoglobin and PLT counts to normal, followed removal of the IUD., Conclusion: The patient's recovery after removal of the IUD and the PEG dependence of RBC agglutination suggested a possibility that the IUD may have been a contributing factor to the etiology of Evans syndrome in this patient., (© 2014 AABB.)

Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe acquired ADAMTS13 deficiency experience one or more relapses. Risk factors for relapse other than severe ADAMTS13 deficiency and ADAMTS13 autoantibodies are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This cross-sectional study asked whether autoantibodies against RNA-binding proteins or peripheral blood gene expression profiles measured during remission are associated with history of prior relapse in acquired ADAMTS13-deficient TTP. Peripheral blood from 38 well-characterized patients with autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies and global gene expression. A subset of TTP patients (9 patients, 24%) exhibited a peripheral blood gene signature composed of elevated ribosomal transcripts that associated with prior relapse. A non-overlapping subset of TTP patients (9 patients, 24%) displayed a peripheral blood type I interferon gene signature that associated with autoantibodies to RNA-binding proteins but not with history of relapse. Patients who had relapsed bimodally expressed higher HLA transcript levels independently of ribosomal transcripts. Presence of any one potential risk factor (ribosomal gene signature, elevated HLA-DRB1, elevated HLA-DRB5) associated with relapse (OR = 38.4; p = 0.0002) more closely than any factor alone or all factors together. Levels of immune transcripts typical of natural killer (NK) and T lymphocytes positively correlated with ribosomal gene expression and number of prior episodes but not with time since the most recent episode. Flow cytometry confirmed elevated expression of cell surface markers encoded by these transcripts on T and/or NK cell subsets of patients who had relapsed. These data associate elevated ribosomal and immune transcripts with relapse history in acquired, ADAMTS13-deficient TTP.

Many patients with syndromes of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, have been reported to have a drug-induced etiology, and many different drugs have been suspected as a cause of TMA. We established criteria to assess the strength of evidence for a causal association of a drug with TMA and systematically searched for all published reports of drug-induced TMA. We identified 1569 articles: 604 were retrieved for review, 344 reported evaluable data for 586 individual patients, 43 reported evaluable data on 46 patient groups. Seventy-eight drugs were described; 22 had evidence supporting a definite causal association with TMA. Three drugs accounted for 61 of the 104 patient reports with definite evidence (quinine, 34; cyclosporine, 15; tacrolimus, 12). Twenty additional drugs had evidence supporting a probable association with TMA. These criteria and data can provide support for clinicians evaluating patients with suspected TMA., (© 2015 by The American Society of Hematology.)

When a pregnant or postpartum woman presents with sudden and severe microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, three syndromes that require urgent care must be considered: (1) preeclampsia with severe features/hemolysis, elevated liver function tests, low platelets (PE/HELLP) syndrome; (2) thrombotic thrombocytopenic purpura (TTP); and (3) complement-mediated thrombotic microangiopathy (C-TMA; also referred to as atypical hemolytic-uremic syndrome). The distinction among these three syndromes is often unclear because they share multiple clinical features. Overlap between PE/HELLP syndrome and the other two syndromes is also apparent from the fact that pregnancy can be a trigger for both TTP and C-TMA both before and after delivery and also the increased frequency of PE/HELLP syndrome in women who have recovered from TTP. When diagnostic criteria for PE/HELLP syndrome are present, management of hypertension and delivery is curative. Absence of improvement or actual progression of MAHA, thrombocytopenia, and kidney function abnormalities after delivery requires consideration of TTP and C-TMA. Minimal kidney involvement with severe thrombocytopenia suggests TTP and the need for treatment with plasma exchange; progressive kidney injury (in the absence of a cause for acute tubular necrosis) suggests C-TMA and the need for anti-complement treatment. We describe how we use these criteria to evaluate and manage pregnant/postpartum women with MAHA and thrombocytopenia., (© 2015 by The American Society of Hematology. All rights reserved.)

Unlabelled: Pregnancy may precipitate acute episodes of thrombotic thrombocytopenic purpura (TTP), but pregnancy outcomes in women who have recovered from acquired TTP are not well documented. We analyzed pregnancy outcomes following recovery from TTP associated with acquired, severe ADAMTS13 deficiency (ADAMTS13 activity <10%) in women enrolled in the Oklahoma TTP-HUS Registry from 1995 to 2012. We also systematically searched for published reports on outcomes of pregnancies following recovery from TTP associated with acquired, severe ADAMTS13 deficiency. Ten women in the Oklahoma Registry had 16 subsequent pregnancies from 1999 to 2013. Two women had recurrent TTP, which occurred 9 and 29 days postpartum. Five of 16 pregnancies (31%, 95% confidence interval, 11%-59%) in 3 women were complicated by preeclampsia, a frequency greater than US population estimates (2.1%-3.2%). Thirteen (81%) pregnancies resulted in normal children. The literature search identified 382 articles. Only 6 articles reported pregnancies in women who had recovered from TTP associated with acquired, severe ADAMTS13 deficiency, describing 10 pregnancies in 8 women. TTP recurred in 6 pregnancies., Conclusions: With prospective complete follow-up, recurrent TTP complicating subsequent pregnancies in Oklahoma patients is uncommon, but the occurrence of preeclampsia may be increased. Most pregnancies following recovery from TTP in Oklahoma patients result in normal children.

Background: Management options for patients with primary immune thrombocytopenia (ITP) have increased, and treatment of patients with ITP has changed during the past 10 years., Methods: To document current practice and to determine how current practice is related to recommendations of 2 recent practice guidelines for ITP, an International Consensus report and an American Society of Hematology (ASH) guideline, the authors surveyed practicing hematologists-oncologists in Oklahoma. Surveys were specific for children or adults. Each survey had 3 questions describing patients with a new diagnosis and patients who had not achieved remission with initial treatment. Questions were adapted from the clinical scenarios of the ASH guideline., Results: Twelve (92%) Oklahoma pediatric hematologists-oncologists responded; 82 (81%) Oklahoma adult hematologists-oncologists responded. For a child with a new diagnosis of ITP, a platelet count of 8000/µL and minor bleeding, 5 (42%) hematologists-oncologists selected observation without drug treatment (recommended by both guidelines). For an adult with a platelet count of 9000/µL who had failed to respond to initial treatment with corticosteroids and IVIg, 32 (39%) selected splenectomy (recommended by the ASH guideline); 30 (37%) selected rituximab and 13 (16%) selected thrombopoietin-receptor agonists (both recommended by the International Consensus report). Hematologists-oncologists who had more years in practice were more likely to select splenectomy (P = 0.047)., Conclusions: In a time of changing management for patients with ITP, these data document reported current management in Oklahoma and provide a basis for serial comparisons across time and for comparisons with other regions and comparison of management with patient outcomes.

Objectives: To determine the frequency of pulmonary involvement in patients with thrombotic thrombocytopenic purpura (TTP)., Methods: The experience of the Oklahoma TTP-HUS (hemolytic-uremic syndrome) Registry, a population-based cohort of consecutive patients without selection or referral bias, 1995-2012, was analyzed. Evidence for pulmonary involvement in patients with TTP was also documented with a systematic review of published reports., Results: Only one of 74 Registry patients with acquired severe ADAMTS13 deficiency (activity <10%) had clinically important pulmonary involvement (transient PaO2 , 42 mm Hg; arterial O2 saturation, 78%; normal chest X-ray). No clinically important pulmonary involvement occurred in the remaining 73 patients. The systematic review identified 144 articles with search terms for TTP and pulmonary involvement; seven, published 1978-2002, had evaluable individual patient data. Five articles described single patients; only one patient was documented to have severe acquired ADAMTS13 deficiency; in none of the five patients was pulmonary involvement clearly related to TTP. Two articles were case series of seven patients each; no patients had ADAMTS13 activity measured. Each of the 14 patients had potential etiologies other than TTP for pulmonary involvement., Conclusions: Only one of 74 patients in the Oklahoma Registry had clinically important pulmonary involvement. A systematic review of published reports documented no clear evidence for pulmonary involvement resulting from TTP. Clinically important pulmonary involvement may be rare in patients with TTP because (i) pulmonary microvasculature may be inherently resistant to the formation of platelet thrombi and (ii) pulmonary function can be maintained in spite of multiple microvascular thrombi., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The growing influence of practice guidelines has increased concern for potential sources of bias. Two recent guidelines for primary immune thrombocytopenia (ITP) provided a unique opportunity for a systematic comparison of different methods of practice guideline development. One guideline (International Consensus Report [ICR]) was supported by pharmaceutical companies that produce products for ITP. The ICR panel members were selected for expertise in ITP; 16 (73%) reported associations with pharmaceutical companies. The other guideline was sponsored by the American Society of Hematology (ASH); panel members were selected for lack of conflicts and for expertise in guideline development as well as for ITP. Discrepancies were conspicuous when the guidelines addressed treatment. In contrast to the ASH guideline, the ICR gave stronger recommendations for agents manufactured by companies from which the ICR or its panel members received support. These data provide direct evidence that differences in financial support and methods of evidence evaluation can influence recommendations.

Background: Acute, immune-mediated thrombocytopenia may be caused by many different approved drugs as well as by other substances including vaccines, complementary and alternative medicines, herbal remedies, nutritional supplements, foods and beverages. All causes are described as drug-induced thrombocytopenia (DITP). Often the cause is not recognized, resulting in recurrent thrombocytopenia and inappropriate treatments. Systematic analysis of children (age less than 18 years) with suspected DITP has not been previously reported., Procedures: (1) We searched 15 databases to identify articles describing children with thrombocytopenia as an adverse effect of drugs and other substances. Articles were reviewed to assign levels of evidence for an association of the suspected substance with thrombocytopenia. (2) Data from the BloodCenter of Wisconsin were reviewed to identify reports of drug-dependent, platelet-reactive antibodies in children with suspected DITP., Results: Of 2,191 articles identified, 242 were selected for review. Seventy-two articles reporting 74 individual patients and nine groups of patients had evaluable data. Eleven individual patients and one group had definite evidence and 40 patients and three groups had probable evidence for an association of the suspected substance with thrombocytopenia. Thirty-two substances had a definite or probable association with thrombocytopenia. During 2008-2012, sera from 91 children with suspected DITP were tested and 21 had drug-dependent, platelet-reactive antibodies involving six substances., Conclusions: Drugs and other substances must be considered as potential causes of thrombocytopenia. Evidence from published reports and data for drug-dependent, platelet-reactive antibodies can help clinicians evaluate of children with unexpected thrombocytopenia., (© 2013 Wiley Periodicals, Inc.)

Background: Thrombotic thrombocytopenic purpura (TTP) associated with severe, acquired ADAMTS13 deficiency is uncommonly reported in children. The incidence, demographic, and clinical features of these children, compared to adults, have not been described., Procedures: This study focused on children (<18 years old) and adults with TTP associated with severe, acquired ADAMTS13 deficiency, defined as activity <10%. The incidence rates for TTP in children and adults were calculated from patients enrolled in the Oklahoma TTP-HUS (Hemolytic-Uremic syndrome) Registry, 1996-2012. To describe demographic and clinical features, children with TTP were also identified from a systematic review of published reports and from samples sent to a reference laboratory for analysis of ADAMTS13., Results: The standardized annual incidence rate of TTP in children was 0.09 × 10(6) children per year, 3% of the incidence rate among adults (2.88 × 10(6) adults per year). Among the 79 children who were identified (one from the Oklahoma Registry, 55 from published reports, 23 from the reference laboratory), TTP appeared to be more common among females, similar to the relative increased frequency of women among adults with TTP, and more common in older children. Clinical data were available on 52 children; the frequency of severe renal failure, relapse, treatment with rituximab, and systemic lupus erythematosus in these children was similar to adults with TTP., Conclusions: TTP associated with severe, acquired ADAMTS13 deficiency is uncommon in children. The demographic and clinical features of these children are similar to the features of adults with TTP., (Copyright © 2013 Wiley Periodicals, Inc.)

Recovery from acute episodes of thrombotic thrombocytopenic purpura (TTP) appears complete except for minor cognitive abnormalities and risk for relapse. The Oklahoma TTP-HUS (hemolytic uremic syndrome) Registry enrolled 70 consecutive patients from 1995 to 2011 with ADAMTS13 activity <10% at their initial episode; 57 survived, with follow-up through 2012. The prevalence of body mass index (BMI), glomerular filtration rate (GFR), urine albumin/creatinine ratio (ACR), hypertension, major depression, systemic lupus erythematosus (SLE), and risk of death were compared with expected values based on the US reference population. At initial diagnosis, 57 survivors had a median age of 39 years; 45 (79%) were women; 21 (37%) were black; BMI and prevalence of SLE (7%) were greater (P < .001) than expected; prevalence of hypertension (19%; P = .463) was not different. GFR (P = .397) and ACR (P = .793) were not different from expected values. In 2011-2012, prevalence of hypertension (40% vs 23%; P = .013) and major depression (19% vs 6%; P = .005) was greater than expected values. Eleven patients (19%) have died, a proportion greater than expected compared with US and Oklahoma reference populations (P < .05). TTP survivors may have greater risk for poor health and premature death.

Drug-induced immune thrombocytopenia (DITP) is a challenging clinical problem that is under-recognized, difficult to diagnose and associated with severe bleeding complications. DITP may be caused by classic drug-dependent platelet antibodies (eg, quinine); haptens (eg, penicillin); fiban-dependent antibodies (eg, tirofiban); monoclonal antibodies (eg, abciximab); autoantibody formation (eg, gold); and immune complex formation (eg, heparin). A thorough clinical history is essential in establishing the diagnosis of DITP and should include exposures to prescription medications, herbal preparations and even certain foods and beverages. Clinical and laboratory criteria have been established to determine the likelihood of a drug being the cause of thrombocytopenia, but these criteria can only be applied retrospectively. The most commonly implicated drugs include quinine, quinidine, trimethoprim/sulfamethoxazole and vancomycin. We propose a practical approach to the diagnosis of the patient with suspected DITP. Key features are: the presence of severe thrombocytopenia (platelet nadir <20×10(9)/L); bleeding complications; onset 5 to 10days after first drug exposure, or within hours of subsequent exposures or after first exposure to fibans or abciximab; and exposure to drugs that have been previously implicated in DITP reactions. Treatment involves stopping the drug(s), administering platelet transfusions or other therapies if bleeding is present and counselling on future drug avoidance. The diagnosis can be confirmed by a positive drug re-challenge, which is often impractical, or by demonstrating drug-dependent platelet reactive antibodies in vitro. Current test methods, which are mostly flow cytometry-based, must show drug-dependence, immunoglobulin binding, platelet specificity and ideally should be reproducible across laboratories. Improved standardization and accessibility of laboratory testing should be a focus of future research., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Hereditary thrombotic thrombocytopenic purpura, Upshaw-Schulman syndrome, ADAMTS13 Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome, is a rare recessively inherited disease. Underlying is a severe constitutional deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, due to compound heterozygous or homozygous mutations in the ADAMTS13 gene. The clinical picture is variable and more and more patients with an adult-onset are diagnosed. In the majority of countries the only available treatment is plasma, which when administered regularly can efficiently prevent acute disease bouts. The decision to initiate regular prophylaxis is often not easy, as evidence based guidelines and long term outcome data are lacking. Through the hereditary TTP registry (www.ttpregistry.net, ClinicalTrials.gov identifier: NCT01257269), which was initiated in 2006 and is open to all patients diagnosed with Upshaw-Schulman syndrome and their family members, we aim to gain further information and insights into this rare disease, which eventually will help to improve clinical management of affected patients.

The Oklahoma Thrombotic Thrombocytopenic Purpura-Haemolytic Uraemic Syndrome (TTP-HUS) Registry has a 24 year record of success for collaborative clinical research, education, and patient care. This article tells the story of how the Registry began and it describes the Registry's structure and function. The Registry provides a model for using a cohort of consecutive patients to investigate a rare disorder. Collaboration between Oklahoma, United States and Bern, Switzerland has been the basis for successful interpretation of Registry data. Registry data have provided new insights into the evaluation and management of TTP. Because recovery from acute episodes of TTP has been assumed to be complete, the increased prevalence of hypertension, diabetes, depression, and death documented by long-term follow-up was unexpected. Registry data have provided opportunities for projects for students and trainees, education of physicians and nurses, and also for patients themselves. During our follow-up, patients have also educated Registry investigators about problems that persist after recovery from an acute episode of TTP. Most important, Registry data have resulted in important improvements for patient care.

When a patient presents with unexpected microangiopathic hemolytic anemia and thrombocytopenia, the diagnosis of thrombotic thrombocytopenic purpura (TTP) is often considered. However, many different disorders, including many different systemic infections and malignancies, can cause thrombotic microangiopathy (TMA), with the clinical features of microangiopathic hemolytic anemia and thrombocytopenia. Other etiologies include severe hypertension, preeclampsia, systemic lupus erythematosus, adverse drug reactions, allogeneic hematopoietic stem cell transplantation, and abnormalities of complement regulation. This article focuses on distinguishing TTP from other etiologies of microangiopathic hemolytic anemia and thrombocytopenia, because consideration of the diagnosis of TTP requires an urgent decision for the initiation of plasma exchange treatment. Awareness of the many etiologies of TMA is essential for the appropriate evaluation of patients presenting with microangiopathic hemolytic anemia and thrombocytopenia and the appropriate diagnosis of TTP., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: The role of bone marrow examinations in patients with primary immune thrombocytopenia (ITP) is uncertain. The objectives of this study were to determine the inter-rater reliability of bone marrow examinations and to identify distinguishing morphological features of ITP bone marrows under controlled conditions., Methods: Histological slides of bone marrow biopsy specimens and aspirates from 32 adult patients with severe primary ITP who had failed a median of two treatments, and 51 non-thrombocytopenic controls were retrieved from hospital archives. Slides were arranged in random order in a slide box and coded. Blinded to the diagnosis and platelet counts, three independent hematopathologists were asked to identify the ITP bone marrows and to evaluate megakaryocyte number, morphology, and distribution., Results: Overall chance-corrected agreement on ITP classification among the three raters was poor [kappa (κ) = 0.30; 95% confidence interval 0.22-0.38]. Raters were generally unable to correctly identify the ITP bone marrows from controls. Increased number of megakaryocytes, while an uncommon finding, was more frequent among ITP patients compared with controls (6/32, 18.8%; vs. 2/51, 3.9%; P = 0.05), and abnormal megakaryocyte morphology often led individual raters to reach a diagnosis of ITP. Overall sensitivity and specificity of bone marrow examinations were 24% and 90%, respectively., Conclusions: This study confirms methodologically that bone marrow examinations are unreliable and frequently non-diagnostic in ITP. Thus, they are not useful for patients with typical disease. Rare subsets of patients with severe ITP demonstrated unique features such as increased number of megakaryocytes., (© 2012 John Wiley & Sons A/S.)

To determine the prevalence of immune thrombocytopenia (ITP) in Oklahoma regardless of age, clinical characteristics, insurance status, and source of health care. Patients with ITP were identified by the administrative code ICD-9-CM 287.3 in Oklahoma hematologists' offices for a 2-year period, 2003-2004. Prevalence was estimated separately for children (<16 years old) and adults because of their distinct clinical characteristics. Oklahoma census data for 2000 was used as the denominator. Eighty-seven (94%) of 93 eligible Oklahoma hematologists participated; 620 patients with ITP were identified. The average annual prevalences were as follows: 8.1 (95% CI: 6.7-9.5) per 100,000 children, 12.1 (95% CI: 11.1-13.0) per 100,000 adults, and 11.2 (95% CI: 10.4-12.0) per 100,000 population. Among children and adults less than age 70 years, the prevalence was greater among women. Among adults aged 70 years and older, the prevalence was greater among men. The highest prevalence of ITP was among men age 80 years and older. These data document for the first time the prevalence of ITP regardless of age, clinical characteristics, insurance status, and source of health care. The methodology developed for this prevalence analysis may be adaptable for epidemiologic studies of other uncommon disorders which lack specific diagnostic criteria and are treated primarily by medical specialists. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc.)

The objective of this study is to establish a method to identify patients with primary immune thrombocytopenia (ITP) utilizing administrative data from diverse data sources that would be appropriate for epidemiologic studies of ITP, regardless of patients' age and source of health care. Medical records of the Oklahoma University Medical Center, 1995-2004, were reviewed to document the accuracy of the administrative code ICD-9-CM 287.3 for identifying children and adults with ITP, using novel, explicit levels of evidence to identify patients with a definite diagnosis. The proportion of patients diagnosed by hematologists compared to non-hematologists and the proportion of patients diagnosed as outpatients compared to inpatients were determined. For children, age <16 years, 323 outpatient medical records were reviewed; 225 adult outpatient medical records were reviewed. The positive predictive value for the administrative code for identifying patients with a definite diagnosis of ITP by a hematologist was 0.72 in children and 0.69 in adults. In 98% of children and 92% of adults seen as outpatients, the definite diagnosis of ITP was established by a hematologist. One hundred eighteen child and 141 adult inpatient medical records were reviewed. In 95% of children and 83% of adults, the definite diagnosis of ITP by a hematologist was established as an outpatient. This study confirmed the previously reported positive predictive value for the administrative code for identifying patients with ITP. Additionally, it was determined that analysis of hematologists' outpatient administrative codes identified most children and adults with ITP. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc.)

Hereditary thrombotic thrombocytopenic purpura (TTP) may be rare, but it is forever. What is the future for our patients?

In this study we examine the mechanisms of dynamic DNA methylation of the p15(ink4b) tumor suppressor gene. Using conventional ChIP and ChiPseq, we identify the p15(ink4b) promoter as a target for the ZNF217 oncogene, the CoREST complex, and DNMT3A. Treatment of cells with TGF-β triggers active demethylation involving loss of ZNF217/CoREST/DNMT3A and the corecruitment of SMAD2/3, CBP, and the DNA glycosylase TDG. Knockdown of TDG, or its functional homolog MBD4, prevents TGF-β-dependent demethylation of p15(ink4b). DNA immunoprecipitation of 5mC and 5hmC indicates that 5mC undergoes conversion to 5hmC prior to activation of p15(ink4b). Remarkably, overexpression of ZNF217 inhibits active demethylation and expression of the p15(ink4b) gene by preventing recruitment of SMAD2/3 and TDG. These findings suggest that active demethylation is essential for regulating a subset of TGF-β-dependent genes. Importantly, disruption of active demethylation by the ZNF217 oncogene may be a paradigm for other oncogenic signals on DNA methylation dynamics., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Management of adults with primary immune thrombocytopenia (ITP) has changed dramatically in the past 10 years. New regimens of corticosteroids for first-line treatment have been introduced and are currently being evaluated in a randomized clinical trial. Many patients may not have durable remissions with initial corticosteroid regimens and may require additional, second-line, treatment. For these patients, rituximab has been increasingly used, as it has for other autoimmune disorders, and new thrombopoietin (TPO)-receptor agonists have been developed. Although splenectomy was the first effective and remains the most effective treatment for ITP, inducing durable complete remissions in 66% of patients, rituximab and TPO-receptor agonists are now additional options for second-line treatment. For patients who continue to have severe and symptomatic thrombocytopenia following failure of multiple treatments, including splenectomy and rituximab, the TPO-receptor agonists are effective as third-line treatment for maintaining safe platelets counts to prevent bleeding symptoms in most patients., (Copyright © 2012 Wiley Periodicals, Inc.)

Although treatment with plasma exchange increased the survival of patients with thrombotic thrombocytopenia purpura to 80% in the 1980s, no further increase of survival occurred over the next 20 years. However, more consistent use of adjuvant treatment with corticosteroids and rituximab in recent years has begun to further increase survival as well as decrease the frequency of relapse. With adjuvant treatment, durable remissions can be achieved more quickly, requiring fewer days of plasma exchange. Fewer days of plasma exchange have resulted in fewer complications, such as central venous catheter-related systemic infections. Future potential options for adjuvant treatment, recombinant ADAMTS13 to correct severe ADAMTS13 deficiency, and agents to block von Willebrand factor-mediated platelet thrombosis are being investigated., (Copyright © 2012 Wiley Periodicals, Inc.)